JPH02202857A - Aminoalkoxybenzene derivative - Google Patents

Abstract

PURPOSE:To obtain a remedy for dysuria, containing aminoalkoxybenzene derivatives including a new compound and salts thereof as principal ingredients, having reducing action on urethratretic tension with low toxicity, capable of selectively reducing urethral resistance without causing hypotensive action and useful for prostatic hypertrophy. CONSTITUTION:A remedy for dysuria obtained by containing a compound expressed by formula I [R<1> is H, hydroxyl, etc.; Q is formula II (R<2> is alkyl, cycloalkyl, etc.; R<3> is H, alkyl, etc.; m is 0, 1 or 2), etc.; n is 2, 3, etc.] and salts thereof as principal ingredients. For example, the compound expressed by formula I is obtained by reacting a compound expressed by formula III (X is halogen) with an amine expressed by formula IV. The compounds expressed by formulas III and IV include new compounds. The compound expressed by formula I is directly administered or contained in an amount of, e.g. 0.1-99.5%, preferably 0.5-90%, in a carrier and administered to animals including humans.

Description

[Detailed description of the invention]

[Industrial Field of Application] The present invention relates to an aminoalkoxybenzene derivative represented by the following general formula (I) and a pharmacologically acceptable salt thereof. Here, R1 is hydrogen, hydroxy, methoxy, acetyl, acetyloxy, isopropoxycarboxy, (2
-imidacylin-2-yl)methoxy, guanidino, thiourido-acetylamino or halogen. n represents 2 or 3. The above-mentioned compound according to the present invention exhibits an effect of lowering urethral closure pressure and is useful as a therapeutic agent for urinary disorder. Therefore, the present invention also relates to a new therapeutic agent for urinary disorder. [Prior Art] Conventionally, the number of pharmaceuticals used as therapeutic agents for urinary disorders has been extremely small, and the emergence of new pharmaceuticals has been eagerly awaited. It has been recognized that α-adrenergic receptors are abundant in the human bladder neck, urethral smooth muscle, and prostatic urethra.
Its importance has been recognized. On the other hand, compounds similar to the compounds of the present invention include, for example, α
- Moxicillate hydrochloride, a blocker and cerebral circulation improver (
moxilyte), and clinical trial data have reported that it is effective in treating urinary disorders (Pedersen B, et al, Acta
Neurol, 5cand, 61107 (1980)
other). However, this substance also has a blood pressure lowering effect,
It could not be said to have low toxicity, and there were problems with its sharpness as a medicine. In addition, 5-[
(3-piperidino)propoxy]-p-cymene derivatives are disclosed as therapeutic agents for urinary disorders associated with plateau pressure. Furthermore, 2-(4-chloro-2-isopropyl-5
It has been reported that methylphenoxy)-N-benzyl-N-ethylethylamine has a hypotensive effect (Ar
Zneim, Forsh, 17305 (1967))
. Additionally, JP-A-56-0100745 discloses compounds similar to the present invention as synthetic intermediates,
Nothing is disclosed that suggests a pharmacological action of the present invention.

[Problem to be solved by the invention]

Based on the above-mentioned prior art, the present inventors have conducted research with the aim of obtaining a compound that does not have a blood pressure lowering effect and has a therapeutic effect on urinary disorders that is superior to conventionally known therapeutic agents for urinary disorders. Ta. Therefore, the problem to be solved by the present invention is to develop an excellent therapeutic agent for urinary disorders.

[Means to solve the problem]

As a result of extensive research, the present inventors have discovered that the compound represented by the above general formula (I) has an excellent therapeutic effect on urinary disorders, and have completed the present invention. One of the gist of the present invention lies in the structure itself of the compound represented by the general formula (1). Among the compounds represented by the general formula (I), compounds in which R1 is hydroxy, n is 2, and N-benzyl-N-methylamino, R' is acetylamino, and n is 2.0 N-benzyl. The compounds in which -N-methylamino and the compounds in which R' is chlorine, n is 2, and Q is N-benzyl-N-ethylamino are known compounds as described above. However, the compounds according to the present invention other than the above three compounds are new compounds that have not been described in any literature. The compound of the present invention represented by general formula (I) has excellent medicinal efficacy as described below and has low toxicity. Therefore, another gist of the present invention is to use the compound represented by formula (I) as the main component of a pharmaceutical composition. The structure of the compound according to the present invention will be explained in detail below. In general formula (I), examples of the halogen represented by R1 include chlorine, bromine, fluorine, and iodine. In general formula (I), the alkyl represented by R2 in 0 is preferably a straight or branched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n- Examples include butyl, isobutyl, 5ec-butyl, tert-butyl, n-pentyl, n-hexyl, and the like. The cycloalkyl preferably has 5 to 7 carbon atoms, such as cycloalkyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Aryl represented as R2 includes phenyl and the like. Examples of the aromatic heterocycle include pyridine. The alkyl represented by R3 is preferably a straight or branched alkyl having 1 to 4 carbon atoms, such as methyl,
Examples include ethyl, hapropyl, isopropyl, n-butyl, isobutyl, 5ec-butyl, tert-butyl and the like. The alkoxy is preferably a linear or branched one having 1 to 4 carbon atoms, such as methoxy, ethoxy, n-propoxy, impropoxy, butoxy,
Examples include isobutoxy and 5eC-butoxy. Examples of halogen include chlorine, bromine, fluorine, and iodine. Examples of the salts of the compounds of the present invention include salts of mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid, oxalic acid, tartaric acid, maleic acid, fumaric acid, methanesulfonic acid, benzenesulfonic acid,
Examples include salts of organic acids such as 1,5-naphthalenedisulfonic acid. The compound of the present invention can be produced, for example, by the following method. Method A (In the formula, R'%Q, 11% are the same as above. X represents a halogen) Method B (V) (In the formula, R1, mouth, and nSX are the same as above.) Method C (■) (I a) (In the formula, 0 and n are the same as above.) NH(Ib) (In the formula, 0 and n are the same as above.) Each production method will be explained in detail below. Method A (I) (I) can be produced by reacting a compound represented by [[) with an amine (IV) in a solvent inert to the reaction in the presence of a base. As reaction solvents, lower alcohols such as methanol, ethanol, and propatool, ketones such as acetone and methyl ethyl ketone, glymes such as methyl cellosolve and ethylene glycol dimethyl ether, ethers such as diethyl ether, dioxane, and tetrahydrofuran, methylene chloride, Halogenated hydrocarbons such as chloroform, hydrocarbons such as benzene, toluene, and xylene, polar solvents such as acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, or a mixed solvent thereof can be used. Bases include alkali metal hydrogen carbonates (e.g., sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), alkali metal carbonates (e.g., sodium hydrogen carbonate, potassium hydrogen carbonate, etc.),
(e.g., potassium carbonate, sodium carbonate, etc.), inorganic bases of alkali metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, etc.), triethylamine, N-methylmorpholine, N-methylpiperidine, pyridine, alkali alkoxides. Organic bases such as salts (eg, sodium ethoxide) can be used. If necessary, the reaction may be carried out by adding 1 to 1.5 times the molar amount of sodium iodide or potassium iodide to accelerate the reaction. The reaction temperature is not particularly limited, but
Usually, the temperature is from room temperature to about 150°C. Amine (IV)
is usually used in an amount equal to or more than 1 mole, preferably 1 to 1.2 times the mole of (■). The amount of base used is (In)
It is preferable to use 1 to 1.2 times the mole per mole. Method B: ('I) can be produced by reacting compound (V) and compound (VI) in a solvent inert to the reaction in the presence of a base. Reaction solvents include water, lower alcohols such as methanol, ethanol, and propatool, ketones such as acetone and methyl ethyl ketone, halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform, and aromatic carbons such as benzene, toluene, and xylene. Hydrogens, ethers such as diethyl ether, dioxane, and tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, and mixed solvents thereof can be used. Examples of bases include alkali hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.), alkali carbonate (e.g., sodium carbonate, potassium carbonate, etc.), alkali borohydride (
Inorganic bases such as alkali alkoxides (eg, sodium ethoxide), organic bases such as triethylamine, morpholine, N-ethylpiperazine, etc. can be used. The reaction temperature is usually 20-150°C, preferably 50-150°C.
The temperature is 65°C. The amount of (Vl) used is usually 1 to 3 times the mole, preferably 1 to 1.5 times the mole of compound (V). The amount of base to be used is usually 1 to
It is 3 times the mole, preferably 1.5 to 2.5 times the mole. In addition, using 1 to 1.2 times the mole of (Vl), in a two-layer solvent containing a catalyst such as a quaternary ammonium salt (e.g., triethylammonium chloride) (40% sodium hydroxide aqueous solution - methylene chloride The reaction can also be carried out by phase transition in a mixed solvent of equal amounts of The reaction temperature is usually room temperature to 150°C, and the reaction time is
It takes from several hours to about 20 hours. Method C A compound having a ureido group in R1 can be produced by converting the compound (■) into a ureido group. Conversion to the ureido group is carried out using an alkali metal salt of thiocyanate (
e.g., sodium salt, potassium salt). The solvent is not particularly limited, but aromatic hydrocarbons such as benzene, toluene, and xylene, halogenated hydrocarbons such as chloroform and methylene chloride, and ethers such as tetrahydrofuran and dioxane are preferred. Usually, the reaction temperature is 0 to 150°C and the reaction time is 0.5 to 5 hours. The amount of metal salt of thiocyanate and trifluoroacetic acid to be used is preferably twice the molar amount of (■). Method D A compound having a guanidino group in R1 can be produced by converting the compound (■) into a guanidino group. Conversion to a guanidino group is carried out by reacting (■) in an acidic aqueous solution with cyanamide. The reaction temperature is room temperature to 100°C, and the reaction time is 0.5 to several hours. The amount of cyanamide used is 5 to 4 for (■)
It is 0 times the mole. Compounds having an acetyloxy group, an isobroboxycarbonyloxy group, or a (2-imidacylin-2-yl)methoxy group in R' are the compounds (■) in which R1 is a hydroxy group obtained as above, respectively. oxy group,
It can also be produced by converting it into an isopropoxycarbonyloxy group or a (2-imidacillin-2-yl)methoxy group. (■) ([c) (In the formula, Q and n are the same as above., R4 represents acetyloxy, isopropoxycarbonyloxy, or (2-imidacylin-2-yl)methoxy.) This reaction , in the presence of a base in a solvent inert to the reaction, the respective corresponding halides (e.g., acetyl chloride, isopyropylchlorocarbonate, (2-imidacyline-
(2-yl)methyl chloride). This reaction can be carried out under substantially the same conditions as the method. The reaction temperature is preferably 0 to 150°C. The compound (I) in which R' is a hydroxy group can also be obtained by hydrolyzing the acetyloxy compound (R' is an acetyloxy group) obtained as described above. This hydrolysis reaction is carried out at room temperature to
Perform at 10°C. or 2 to 30 times the amount (preferably 5 to 30 times the amount)
The reaction is carried out by stirring at room temperature to 110° C. in a solution of 1 to 10% potassium hydroxide or sodium hydroxide (10 times the amount) in a hydrous alcohol (methanol, ethanol, propatool, etc.). The starting materials (II[), (IV), (V), and (■) contain new compounds, but these new compounds are
It can be produced in the same manner as a known method or a method described as a reference example described later. The target compound (I) thus produced can be prepared in the form of a free base or in the form of an acid addition salt by means known per se.
For example, it can be isolated and purified by concentration, liquid conversion, dissolution, solvent extraction, crystallization, fractional distillation, chromatography, etc. When the compound of the present invention is administered as a medicament, the compound of the present invention may be administered as is or in a pharmaceutically acceptable non-toxic and inert carrier, for example, 0.1% to 99.5%, preferably 0.5%. It is administered to animals, including humans, as a pharmaceutical composition containing % to 90%. As carriers, one or more solid, semisolid, or liquid diluents, fillers, and other formulation auxiliaries are used. Preferably, the pharmaceutical composition is administered in dosage unit form. The pharmaceutical composition of the present invention can be administered orally, intracellularly, locally (transdermally, etc.), or rectally. Of course, it is administered in a dosage form suitable for these administration methods. For example, oral administration is particularly preferred. It is desirable to adjust the dose as a therapeutic agent for urinary dysfunction, taking into consideration the patient's condition such as age and weight, the route of administration, the nature and severity of the disease, etc. Ingredient amount: 0.1mg to 100 per day
mg/human, preferably from 0.1 to b. In some cases, a lower dose may be sufficient, or on the other hand, a higher dose may be required. It can also be administered in divided doses 2 to 3 times a day. (See next page)

【Example】

The present invention will be explained in more detail with reference to Reference Examples, Examples, Test Examples, and Prescription Examples below. Reference Example 1 190 g of 2-acetyl-5-(2-bromoethoxy Lp-cymene 4-acetylthymol and 902 g of 1,2-cyfuromoethane were mixed in a two-layer system of 40% aqueous sodium hydroxide solution 1°21 and methylene chloride 1.21 g). 114 g of benzylethyl ammonium chloride dissolved in a mixed solvent and cooled on ice.
was added little by little. After stirring at room temperature for 16 hours, the methylene chloride layer is separated. The water layer is further 300mj! of methylene chloride. Combine the two, wash with water, dry over magnesium sulfate, and concentrate. Distill the residue under reduced pressure to obtain 21
2 g of oil was obtained. Boiling point 175-180°C 15mmHg Reference example 2 2-acetoxy-5-(2-bromoethoxy)-p-cymene 2-acetyl-5-(2-bromoethoxy)-p-
Dissolve 100 g of cymene in 1.51 g of toluene and cool with water.
152 g of trifluoroacetic acid is added dropwise at such a rate that the reaction temperature does not rise above 15°C. Next, m-chlorobenzoic acid is added little by little, followed by stirring for 16 hours. After the reaction is completed, 10% ammonia water is added and the toluene layer is separated. The toluene layer is washed successively with a 10% aqueous sodium bisulfite solution, water, and saturated brine, dried, and then concentrated. The residue was distilled under reduced pressure to obtain 89 g of the desired product as a yellow oil. Boiling point: 170° C./gmmHg Reference Example 3 30.0 g of 3-(2-chloroethoxy)-p-cymene (1) thymol, 35.2 g of ethylene carbonate, and 27.6 g of potassium carbonate are heated under reflux in 40 ml of toluene for 4 hours. After cooling, add ice water and separate the toluene layer. Wash with 5% aqueous sodium hydroxide solution, combine the aqueous layer and alkaline layer, and extract again with toluene. Combine the toluene layers and wash with water. After drying and concentrating, the residue was distilled under reduced pressure to obtain 3-(
31.6 g of 2-hydroxyethoxy)-p-cymene was obtained. Boiling point 110-115°C/2mmHg (2) 3-(2-hydroxyethoxy)-p-cymene 3. Og is dissolved in 1.2 g of pyridine, and 1.8 g of thionyl chloride is added dropwise under water cooling. After completion of the dropwise addition, the mixture was heated to 100°C and stirred for 1 hour. After cooling, the reaction solution was poured into cold 10% hydrochloric acid and extracted with chloroform. The extract is washed with water, dried and concentrated. The residue was distilled under reduced pressure to obtain 2.7 g of the target substance as a colorless oil. Boiling point: 104°C, 72 mmHg Reference example 4 N-benzyl-N-ethyl-2-chloroethylamine hydrochloride (1) A mixture of 6.0 g of ethylene bromohydrin, 5.4 g of N-ethylbenzylamine, 10 g of potassium carbonate, and 200 ml of acetonitrile was heated overnight. , and heat to reflux. After the reaction is completed, insoluble matter is filtered off. The filtrate is concentrated, water is added to the residue, and the mixture is extracted with ethyl acetate. The extract is washed with water, dried and concentrated. The residue was distilled under reduced pressure to obtain 2 as a slightly yellow oil.
-(N-benzyl-N-ethylamino)ethanol3.
3g was obtained. Boiling point: 120-125°C, 5 mmHg (2) 3.0 g of 2-(N-benzyl-N-ethylamino)ethanol is dissolved in 30 ml of chloroform, and 5.0 g of thionyl chloride is slowly added dropwise while stirring under water cooling. After completion of the dropwise addition, the mixture was stirred at room temperature for 2 hours and further heated under reflux for 2 hours. After cooling, the solvent is distilled off and ether is added to the residue. The precipitated crystals were collected by filtration, thoroughly washed with ether, and then dried under reduced pressure to obtain 3.7 g of pale yellow crystals. Melting point/
141-142°C Reference Example 5 2-(4-amino-2-isopropyl-5-methylphenoxy)-N-benzyl-N-ethylamine 2-(4
-acetylamino-2-isopropyl-5-methylphenoxy)-N-benzyl-N-ethylamine (Example 2)
34 ml of 6N hydrochloric acid was added to 5.25 g of compound No. 1) and refluxed for 3 hours. After cooling, the pH was adjusted to 8 with a saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. Wash the extract with water,
After drying (magnesium sulfate), ethyl acetate was distilled off under reduced pressure to obtain 4.5 g of a pale brown oil. Example 1 2-(4-acetoxy-2-isopropyl-5-methylphenoxy)-N-benzyl-N-ethylethylamine maleate 2-acetoxy-5-(2-bromoethoxy)-p-cymene 40 g and N - 17 g of ethylbenzylamine and 32 g of triethylamine are dissolved in 400 ml of absolute ethanol and heated under reflux for 20 hours. After cooling, concentrate under reduced pressure, add water to the residue, and extract twice with ethyl acetate. The extract is washed with water, dried, and concentrated. The residue was subjected to silica gel column chromatography and eluted with chloroform.
g of free base was obtained. Dissolve 3.0 g of this in a small amount of ethanol, then dissolve 1.0 g of maleic acid. After adding Og and dissolving it by heating, the mixture was cooled on ice again and crystallized. The crystals were collected by filtration, thoroughly washed with ether, and dried in vacuo to obtain 3.6 g of the desired product as colorless crystals. Melting point 102-10
3℃ elemental analysis value (CsJaJOa・C4) 1.04) Theoretical value C66,7987,27N2.88 Actual value C6
6,6287,22N 2.81 The following compound was obtained by operating in the same manner. Example 2 2-(4-acetyl-2-isopropyl-5-methylphenoxy)-N-benzyl-N-ethylethylamine maleate Melting point 93-94°C Elemental analysis value (C23H-INO2・C,H,0, ) Theoretical value C69,06117,51N2.98 Actual value C6
8,9087,58N 2.97 Example 3 2-(2-isopropyl-5-methylphenoxy)-N
-benzyl-N-ethylethylamine maleate (
1) 3-(2-chloroethoxy)-p-cymene2.
Og to N. Dissolved in 50 ml of N-dimethylformamide and added N
-1.3g of ethylbenzylamine and 2g of sodium iodide
．． Add 1 g and 3.3 g of potassium carbonate, heat to 150°C, and stir for 1 hour. After the reaction is completed, N,N-dimethylformamide is distilled off under reduced pressure and concentrated. Add water to the residue,
Extract twice with ethyl acetate. After washing with water, dry and concentrate. The residue was subjected to column chromatography (silica/chloroform) to obtain 2.7 g of a pale yellow oily substance. Dissolve this in a small amount of ethanol and add 1.1 g of maleic acid.
Add and warm to dissolve. The solvent was distilled off, ether was added to the residue 23, and the mixture was cooled on ice to precipitate maleate. The crystals were collected by filtration, thoroughly washed with ether, and dried to obtain 3.2 g of the target compound as colorless crystals. Melting point 79-81 is elemental analysis value (Cs+HzsNO・C,H,0,) theoretical value C70,23N 7.78 N 3.28 actual value
C69,9387,58N 3.33 Hydrochloride was prepared in the same manner. Melting point 119-120℃ Elemental analysis value (C21H2BNO・HCI) Theoretical value C7
2,49N 8.69N 4.03 Actual value C72
,20H8,68N 4.16(2) Thymol 3.0g
, N-benzyl-N-ethyl-2chloroethylamine hydrochloride 6.2 g, potassium carbonate 10 g 1 acetone 100 m
Heat the mixture of 1 to reflux overnight. After cooling, insoluble materials are removed by filtration and the filtrate is concentrated. Add water to the residue and extract with ethyl acetate. The extract is washed with water, dried and concentrated. The obtained oily substance was converted into a maleate salt by a conventional method to obtain 7.3 g of the target substance. Example 4 2-(4-isopropoxycarboxy-2-isopropyl-5-methylphenoxy)-N-benzyl-N-ethylethylamine maleate 2-(4-hydroxy-2-isopropyl-5-methylphenoxy)- 2.0 g of N-benzyl-N-ethylethylamine is dissolved in 20 ml of ethyl acetate, and 0.92 g of triethylamine is added. Under ice cooling, 0.75 g of isopropyl chlorocarbonate was slowly added dropwise. After the reaction is completed, the reaction solution is washed three times with water, dried, and concentrated. The residue was purified by column chromatography (silica/chloroform) to obtain 1.7 g of a pale yellow oil. Dissolve this in a small amount of ethyl acetate, add 0.51 g of maleic acid, heat to dissolve, cool on ice, add n-hexane, and crystallize. The crystals were collected by filtration, thoroughly washed with isopropyl ether, and then dried in vacuo to form a white powder.
7g was obtained. Melting point 86-88℃ IR (rcm-') 2950 1740
1470 1245 1180 1100 Elemental analysis value (C-s) I-sNO<・C4H10,) Theoretical value C6
5,77H7,42N 2.64 Actual value C65,51
87,39N 2.85 Example 5 2-[4-([(2-imidacillin-2-yl)methoxyco-2-isopropyl-5-, methylphenoxy)
]-]N-ethyl-N-2-methoxybenzyl)ethylamine dihydrochloride 2-(4-hydroxy-2-isopropyl-5-methylphenoxy)-N-ethyl-N=(2-methoxybenzyl)ethylamine 1.2 g Add 70.63 g of 2-chloromethylimidazolyne and 0.4 g of ethylbenzyl ammonium chloride to 20 m of a 40% aqueous sodium hydroxide solution.
j! The mixture was added to a mixed solvent of 40 mIl of methylene chloride and stirred overnight at room temperature. The methylene chloride layer is separated, washed with water, dried, and concentrated. The residue was purified by column chromatography (alumina/chloroform:methanol=50:1) to obtain 0.5 g of an oily substance. This was dissolved in dry ether, and while cooling with water, hydrogen chloride gas was blown into the solution until precipitation was completed to obtain a hydrochloride salt, yielding 0.4 g of colorless crystals. Melting point 70-75℃ IR (KBr cm -') 3400 295
0 1610 1500 1460 1400 Elemental analysis value (C*5HsqNsOs ・2HCI>Theoretical value C6
0.91N7.67 N8.20 Actual value C60.8
5N 7.62 N 8.12 Example 6 4-[2-(N-benzyl-N-ethylamino)ethoxy]5-isopropyl-2-methylphenylthiourea hydrochloride 4-[(N-benzyl-N-ethyl amino) ethoxy]
-2.76 g of 5-isopropyl-2-methylaniline and 1.38 g of sodium thiocyanate were added in 10 g of dry toluene.
m1 and warm to 45-50°C. A solution of 2.13 g of trifluoroacetic acid in 5 ml of dry toluene was added dropwise thereto over about 2 hours, and the mixture was heated under reflux for 2 hours. After cooling, add saturated sodium bicarbonate solution to neutralize, and extract with ethyl acetate. The extract is washed with water, dried and concentrated. Add isopropyl ether to the residue, crystallize it, and filter to obtain 2.6 g of colorless crystals.
I got it. This was dissolved in dry ether and hydrogen chloride gas was passed through it to obtain 2.53 g of hydrochloride as colorless crystals. Melting point 141-144℃ Elemental analysis value (C2Js+Ns mouth S
-1 (CI -820) Theoretical value C60,05H7,
79N 9.55 Actual value C60J3 118.01
N9.32 Example 7 2-(4-guanidino-2-isopropyl-5-methylphenoxy)-N-benzyl-N-ethylethylaminenimethanesulfonate 10 g of cyanamide prepared at the time of use was heated to 60°C. Then, 10 ml of a solution of 2.0 g of 2-(4-amino-2-isopropyl-5-methylphenoxy)-N-benzyl-N-ethylethylamine in 6N hydrochloric acid was slowly added dropwise. After completion of the dropwise addition, stir at 80°C for 30 minutes. After the reaction is completed, the mixture is cooled, neutralized with saturated aqueous sodium bicarbonate, washed with ether, and the aqueous layer is adjusted to pH 9 with saturated aqueous sodium bicarbonate. The precipitated crystals were collected by filtration, washed with water and acetone, and dried to obtain 0.67 g of anhydrous crystals. The obtained crystals are dissolved in methanol and methanesulfonic acid is added. Methanol is distilled off, and ether is added to the residue for crystallization. The crystals were collected by filtration, washed with ether, and dried to obtain 0.75 g of slightly brown crystals. Melting point 85-90℃ Elemental analysis value CC2zHsxN-0・C2)1s06S2
) Theoretical value C51,41N 7.19 N 9.99
Actual value C51,44H7,41N 9.72 Example 8 2-(4-hydroxy-2-isopropyl-5-methylphenoxy)-N-ethyl-N-(2-methoxybenzyl)ethylamine hydrochloride Melting point 128-130°C Elemental analysis value (C, JaJOs ” HCI) theoretical value C67
,0888,19N 3.56 actual value C66,938
8,10N 3.44 Example 9 2-(4-hydroxy-2-isopropyl-5-methylphenoxy)-N-(3-chlorobenzyl)-N-ethylethylamine hydrochloride Melting point 159-161°C Elemental analysis value ( C2+fl*5CINO2・HCI) Theoretical value C
63,32) 17.34 N 3.52 Actual value C6
3,1411'7.34 N 3.46 Example 10 2-(4-acetoxy-2-isopropyl-5-methylphenoxy)-N-benzyl-N=lowpropylethylamine maleate Melting point 88-91°C Elemental analysis Value (C24) 133NO3・C4H404) Theoretical value C67,3L H7,46N 2.80 Actual value C67,15H7,56N 2.79 Example 11 2-(4-acetoxy-2-isopropyl-5-methylphenoxy)-N -Methyl-N-phenethylethylamine maleate Melting point 104-105°C Elemental analysis value (C,,) 1. +, NO, ・CJJn) Theoretical value C66,79N 7.27 N 2.88 Actual value C66,5887J5 N 2.89 Example 12 2-(4-II nitroxy-2-isopropyl-5-methylphenoxy)-N -(2-chlorobenzyl)-N-
Ethyl ethylamine hydrochloride Melting point 179-180℃ Elemental analysis value (Cwt) IzeNO*・HCI) Theoretical value C
63,32H7J4 N 3.52 actual value C63,
26H7JI N 3.46 Example 13 2-(4-acetoxy-2-isopropyl-5-methylphenoxy)-N-ethyl-N-(3-methoxybenzyl)ethylamine maleate Melting point 105-106
°C elemental analysis value (Cm,)H3,NO,・C,)1.0.
) Theoretical value C65,23H7,23N 2.72 Actual value C65°36 H7,25N2.93 Example 14 2-(4-acetoxy-2-isopropyl-5-methylphenoxy)-N-benzyl-N-isopropylethylamine Hydrochloric acid Salt Melting point 68-73℃ Elemental analysis value (C24HO3NOa・HCI) Theoretical value C
68,64N 8.16N 3.33 Actual value C6
8,9088,17N 3.26 Example 15 2-(2-isopropyl-4-methoxy-5-methylphenoxy)-N-benzyl-N-ethylethylamine
Mararuinate Melting point 86-88℃ Elemental analysis value (C,, H3, NO, ・C41 (404) Theoretical value C68,25H7,71N 3.06 Actual value C
67,98) 17.71 N3.30 Example 16 2-(4-acetoxy-2-isopropyl-5-methylphenoxy)-N-ethyl-N-(4-methylbenzyl)ethylamine maleate Melting point 93-94 °C elemental analysis value (Cs4HasNO3・C,H,0,) theoretical value
C67J2 87.46 N 2.80 Actual value C6
7,01H7,35N 3.01 Example 17 2-(4-tnitroxy-2-isopropyl-5-methylphenoxy)-N-benzyl-N-cyclohexylethylamine hydrochloride Melting point 171-172°C Elemental analysis value (Cs4asNO3. 1 (CI) theoretical value C
71,83H8,68N 3.35 Actual value C71,6
5H8,73N 3.61 Example 18 2-(4-acetyl-2-isopropyl-5-methylphenoxy)-N-methyl-N-benzylethylamine maleate Melting point 121-122°C Elemental analysis value (CsJ2sNOt ・C- H404) Theoretical value C6B, 55 87.30 N 3.07 Actual value C68,25B 7.29 N 3J5 Example 19 3-(4-acetyl-2-isopropyl-5-methylphenoxy)-N-benzyl-N- Ethylpropylamine picrate Melting point 105-107℃ Elemental analysis value (C24HsaNO*・C5HaNa)
Theoretical value C60J9 H6,08N 9J9 actual value
C60,3486,15N 9.42 Example 20 2-(4-acetyl-2-isopropyl-5-methylphenoxy)-N=ethyl-N-(3-methoxybenzyl)ethylamine hydrochloride Melting point 163-165°C Elemental analysis Value (C1148-NO8・HCI) Theoretical value C68,
6488,16N 3.34 actual value C68,46H8
,00N 3.59 Example 21 2-(4-acetoxy-2-isopropyl-5-methylphenoxy)-N-benzyl-N-methylethylamine maleate Melting point 96-98°C Elemental analysis value (C2, H,, NO, ・C, H40,) Theoretical value C66,23N 7.05 N 2.97 Actual value C66,1687,12N 3.20 Example 22 2-(4-Cetylminnow 2-isopropyl-5-methylphenoxy )-N-benzyl-N-ethylethylamine hydrochloride Melting point 110-113°C. Elemental analysis value (C*-)1aJJ2 ・HCI) Theoretical value
C68, 2188, 21N 6.92 actual value C67,
94H8J8 N 7.18 Example 23 2-(4-chloro-2-isopropyl-5-methylphenoxy)-N-benzyl-N=ethylethylamine
Maleate salt Melting point 101-103°C Example 24 2-[(4-acetyl-2-isopropyl-5-methylphenoxy)ethylco1.2.3.4-tetrahydroisoquinoline maleate Melting point 179-181°C Elemental analysis value (C23)1211802・C,)1. ) Theoretical value C69,36N 7.11 N 3.00 Actual value C89,3L H7,36N3.19 Example 25 2-[(4-chloro-2-isopropyl-5-methylphenoxy)ethyl]-1, 2,3,4-tetrahydroisoquinoline maleate Melting point 167-168℃ Elemental analysis value (C21826CINO・C4H40-) Theoretical value C65,28H6,57N 3.05 Actual value C64
,9986,83N 3.06 Example 26 2-[(4-hydroxy-2-isopropyl-5-methylphenoxy)ethyl]-1,2,3,4-tetrahydroisoquinoline maleate Melting point 145-146°C
Elemental analysis value (C2IH27NOz・C4H404) Theoretical value CB8.01 N 7.08 N 3.17 Actual value C67,8187,22N 3J4 Example 27 2-[(4-acetoxy-2-isopropyl-5-methylphenoxy)ethyl ]-1,2,3,4-tetrahydroisoquinoline maleate Melting point 153-154℃
Elemental analysis value (C23f12-NOs・C,H,0,) Theoretical value C67,06H6,88N 2.90 Actual value C
66,92,) 1.7.09 N 2.90 Example 2
8 2-[(2-isopropyl-5-methylphenoxy)ethyl]-1,2,3,4-tetrahydroisoquinoline
Maleate Salt Melting point 177-178℃ Elemental analysis value (C21H2?NO・C4H404) Theoretical value C70,57H7J4 N 3.29 Actual value C7
0,46H7,49N 3J4 Example 29 2-(4-hydroxy-2-isopropyl-5-methylphenoxy)-N-benzyl-N-ethylethylamine hydrochloride Melting point 144-145°C. Elemental analysis value (C21H28NO2・)Ice) Theoretical value
C69,311 (8,31N3.85 actual value C69,
41H8,20N 3.76 Example 30 2-(4-hydroxy-2-isopropyl-5-methylphenoxy)-N-benzyl-N-methylethylamine hydrochloride Melting point 143-145°C. Elemental analysis value (C20H27NO2・1 (CI) theoretical value
C6B, 65 N 8.07 N 4.00 Actual value C68,42H8,02N 4.07 Test Examples The results of pharmacological tests showing the usefulness of representative examples of the compounds of the present invention are shown below. Test Method 1, α-Adrenergic Receptor Binding Experiment Receptor membrane preparations were prepared as follows. The rat was decapitated, the whole brain except the cerebellum was removed, and after weighing, 40 volumes of 50d) Lis-HCl buffer (pH 7.4) was added, homogenized with a Polytron homogenizer, and centrifuged at 39.0 OOG for 20 minutes. did. Add a buffer solution to the sediment, suspend it, and repeat 2
After centrifugation for 0 minutes, 40 times the volume of Tris-hydrochloric acid buffer was added to the precipitate to suspend it, and it was used as a receptor membrane preparation. All of the above operations were performed under cooling at 4°C. Measurement of C1-adrenergic receptors was performed using 3H-prazosin as a radioligand and C2-adrenergic receptor.
- Measurement of adrenergic receptors is performed using sH-yohimbine (
yohimbine). First, the receptor membrane preparation of each tissue prepared by the above method was
0mM) in Lis-HCl buffer (pH 7,4) for 3H.
-prazosin (0,2HM) and 3H-yohimbine (1HM) at 25°C for 30 minutes and at 20°C for 60 minutes, respectively. After the incubation was completed, the reaction solution was suction filtered onto glass fiber filter paper (Whatman GF/B). The filter paper was washed three times with 3 ml of ice-cold buffer, transferred to a vial, scintillator 1011 was added, and left at room temperature for about 10 hours or more, and its radioactivity was measured using a liquid scintillation counter. is fully connected (T
total binding). In addition, the same reaction as above was carried out using 1 μM prazosin ('H-p
razosin binding) and 100
μM yohimbine ('H-yohimbine bind
ing), and the resulting radioactivity was used for non-specific binding (Non-specific binding).
The difference between total binding and non-specific binding is defined as specific binding (Spe
cific binding). The above experiment is
Everything was done in duplicate. The inhibitory effect of the drug on the receptor was investigated by measuring the specific binding of the radioligand to the receptor membrane preparation in the presence of various concentrations of the test drug. The % inhibiting drug concentration, ie, IC5o value, was calculated. The results are shown in Table 1. (See next page) 2. Measurement of urethral pressure and blood pressure Experiments were conducted using male rabbits weighing 1.8 to 3.5 kg under fasting conditions. Animals treated with urethane (800mg/kg
. S, C0) After fixation at the site under anesthesia and a midline incision in the lower abdomen, the bladder was exposed. In order to prevent the effect of urine stored in the bladder on the intraurethral pressure, the urine stored in the bladder was forcibly drained out of the body, and then catheters were inserted into the ureters on both sides, and the urine drained from the kidneys was led out of the body. A catheter for measuring urethral pressure with a balloon filled with physiological saline attached to the tip is inserted into the bladder through the external urethral orifice.
This was pulled out at a constant speed toward the external urethral meatus using an automatic pulling unit, and the intraurethral pressure at each part of the urethra was measured. In addition, a polyethylene tube was inserted into the femoral artery, and blood pressure (BP) was also measured. The test drug was administered into the duodenum, and after administration, the maximum urethral constriction pressure (UCPmax) and blood pressure were measured over time. The results are shown in Table 2. We investigated the effects of drugs on urethral pressure using maximum urethral closure pressure as an index. Each value after administration of the test drug was expressed as a percentage of the value before administration. The results are shown in Table 3. (See next page) Table 2 0CPmax (Decrease rate %) Table 3 BP (Decrease rate %) 3. Acutely toxic mice (cldY male, 6-7 weeks old) were used together with 4 mice in - group. The test drug was forcibly administered orally using a probe to animals that had fasted from the day before administration (16-18 hours). After administration of the drug, the animals were returned to a state where they could freely ingest water and food, and the animals were observed for 2 weeks for general symptoms and the appearance of death. The test drug was suspended in physiological saline containing 0.5% methylcellulose and administered orally. Example compounds 1.2.3 and 29 were tested. As a result, all of the example compounds had low toxicity, and no deaths were observed at a dose of 1000 mg/kg. Moxisilito is LD. was 330 mg/kg. As is clear from the above results, the compound of the present invention had a strong urethral closure pressure-lowering effect and selectively reduced urethral resistance without a blood pressure-lowering effect. Toxicity is also extremely low. The compound of the present invention has excellent effects not found in existing pharmaceuticals and has low toxicity, so it can be safely used for the treatment of urinary disorders associated with benign prostatic hyperplasia. Formulation Example 1 1 mg of the compound of Example 1, 60 mg of lactose, 33 mg of corn corn, 15 mg of crystalline cellulose, 10 mg of hydroxypropyl cellulose, and 1 mg of magnesium stearate were taken, and tablets were manufactured according to a conventional method. Formulation Example 2 1 mg of the compound of Example 2, 100 mg of % lactose, 44 mg of Umorocidebune, 1 mg of Aerosil, 3 mg of hydroxypropyl methylcellulose, and 1 mg of magnesium stearate were taken, and capsules were manufactured according to a conventional method. Formulation Example 3 2 mg of the compound of Example 3, 918 mg of lactose, 40 cng of crystalline cellulose, and 400 g of hydroxypropyl cellulose were taken, and fine granules were produced according to a conventional method.

Claims (2)

[Claims] (1) An aminoalkoxybenzene derivative represented by the following general formula (I) and a pharmacologically acceptable salt thereof. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) Here, R^1 is hydrogen, hydroxy, methoxy, acetyl, acetyloxy, isopropoxycarboxy, (
2-imidazolin-2-yl)methoxy, guanidino,
Represents thioureido, acetylamino or halogen. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (R^2 represents alkyl, cycloalkyl, aryl, or aromatic heterocycle. R^3 represents hydrogen, alkyl, alkoxy, halogen. m is 0, Represents 1 or 2.) or ▲Represents mathematical formulas, chemical formulas, tables, etc.▼. n represents 2 or 3. However, when R^1 is hydroxy, n is 2, and Q is N-benzyl-N-methylamino, when R^1 is acetylamino, n is 2, and Q is N-benzyl-N-methylamino , and when R^1 is chlorine, n is 2, and Q is N-benzyl-N-ethylamino. (2) A therapeutic agent for urinary dysfunction comprising as a main component an aminoalkoxybenzene derivative represented by the following general formula (I) and a pharmacologically acceptable salt thereof. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) Here, R^1 is hydrogen, hydroxy, methoxy, acetyl, acetyloxy, isopropoxycarboxy, (
2-imidazolin-2-yl)methoxy, guanidino,
Represents thioureido, acetylamino or halogen. Q has ▲a mathematical formula, a chemical formula, a table, etc.▼ (R^2 represents alkyl, cycloalkyl, aryl, or aromatic heterocycle. R^3 represents hydrogen, alkyl, alkoxy, or halogen. m is , represents 0, 1 or 2) or ▲ represents a mathematical formula, chemical formula, table, etc. ▼. n represents 2 or 3.